I have great news. My son Ace has been released early from the Upshur County jail today. And for what reason we do not know. Although we have our suspicions, we were afraid to ask. We suspect that they may have recorded my son and I talking during jail visitation last night and realized that we were planning to use the fact that his release from jail and the time that I am to put him out of the house per Judge Lauren Parish ruling almost co-existed to our favor in order to request more time, so he could get his feet back on the ground and I could help him some with finances because about one month will pass before he gets a paycheck and he has fallen behind on his truck payment which may be reposessed and his cell phone which has already been shut off. He must have both of these in order to work in his field as a contract cable installer.

My brother Larry has awoken from his Anastasia and is doing quite well for a man who just had his chest ripped open. I know all of you haters who are board members of Gilmer no-Boating and no-Fishing Club must be deeply disappointed, and frankly my dear I just don’t give a damn. And I really don’t care how many people tell me the same old cliché. “You better be careful or somebody is going to end up dead in the woods. It’s happened before.” Because I know, that enough people already know what’s going on, that even District Attorney Billy Byrd can’t get away with murder. By the way Mr. District Attorney Billy Byrd when the feds come in and tell all your little friends that they may go to prison for perjury, they will most likely all squeal like little pigs, and they will all be squealing your name District Attorney Billy Byrd.

Okay here we go, with the last part of my update. I am not the kind of person who does a lot of wining about what is going on with me but since I am trying to be as honest as possible it seems that it would only be fair that I let the readers know. So again, here we go. I have no car. My car was repossessed last month as it was I could do to save our home from foreclosure and pay my Attornys. I will most likely be going into the hospital the first week of June for a blood transfusion because of an extremely rare disorder I have acquired and been struggling with for several years that has been brought on by the stress that the Gilmer Boating and Fishing Club has caused me over the past five years called Pure Red Cell Aplasia. Now you know why death threats don’t scare me. I am already dying. It will be necessary for me to help Ace get a new start after his time in jail and to help Larry get new residence after he gets out of the hospital and to obtain a car. I honestly don’t know if I can do all this but I do know I am willing to die trying.

I was just wondering if you were able to get with IwanaBaDoctor, anonymous the 3rd, ouuuu me too and the other anonymous (you didn’t I knew there were two of you did you) to discuss causes of pure red cell aplaisia, because unless your term paper is about sexually transmitted diseases and drug abuse you are most likely going to flunk.

Calvin_Monasco

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May 14, 2010

Hello readers,

As many of you have pointed out there can be many causes for pure red cell aplasia. As a matter of fact it seems there are nearly as many possible causes as there are opinions in this world. As they say everyone has one and they are all different. I had no idea there were so many of you with such deep interest in medicine. Maybe we could start a club and research other illnesses. Thank you so much for your input. I look forward to hearing from more readers who have great interest in my illness. Good luck with your term paper anonymous. Let me know if I can be of any help. It may help you to interview some with the disease. Look like a lot of other peaople have term papers perhaps you could all get together and interview at once.

anonymous

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May 14, 2010

Thank you! this helped with my term paper. It's a wonderment when you log on to research what all you find.

The data were presented yesterday by Iain C. Macdougall, M.D., Hematide clinical trial investigator, consultant nephrologist and honorary senior lecturer at King's College Hospital in London during an oral presentation at the American Society of Nephrology Renal Week 2007 in San Francisco. In addition, Phase 2 clinical trial results of Hematide in patients with anemia due to CKD were presented during the poster session.

PRCA, a rare autoimmune disorder, occurs when the body produces neutralizing antibodies to the currently marketed recombinant human erythropoietin (EPO), thus suppressing the production of red blood cells by the bone marrow. In contrast, Hematide, Affymax’s lead drug in development for the treatment of anemia, is a novel synthetic, pegylated peptidic compound with no structural homology with human EPO.

“PRCA is a treatment complication resulting when a patient develops antibodies to recombinant EPO products. While rare, PRCA is a serious disease that prohibits further treatment with recombinant EPO and requires patients undergo regular blood transfusions and immunosuppressive therapy to suppress antibody production in an attempt to correct anemia and manage hemoglobin levels,” said Dr. Macdougall, consultant nephrologist in the Department of Renal Medicine at King’s College Hospital in London, U.K. “These trial results provide important information about the safety profile of Hematide.”

“Hematide is immunologically distinct from EPO. In preclinical studies, Hematide addressed hemoglobin deficiencies caused by EPO-specific antibodies, and antibodies generated to recombinant EPO have not been shown to cross-react with Hematide,” added Robert B. Naso, Ph.D., executive vice president of research and development at Affymax. “The PRCA data presented at ASN are intriguing findings which support the differentiation of Hematide. At some point in the future, Affymax and Takeda may decide to pursue further development of the product in the area of PRCA, but for now our development priorities are focused on anemia in chronic renal failure and chemotherapy-induced anemia.”

“We are pleased with this data presentation, which suggests the difference of Hematide,” said Masaomi Miyamoto, Ph.D., general manager of pharmaceutical development division at Takeda. “With our partner Affymax, we will vigorously continue development activities of this scientifically interesting product as a potential new treatment option for patients with anemia in both chronic renal failure and chemotherapy-induced anemia.”

PRCA Study Results

The open-label, multi-center trial in 10 dialysis and predialysis CKD patients with PRCA evaluated the effectiveness and safety of Hematide administered subcutaneously every four weeks. The primary endpoint was the change in hemoglobin from baseline over time. Secondary endpoints included safety and the effectiveness of Hematide in reducing the frequency of red blood cell transfusions over time.

Results showed that by six months of treatment, median hemoglobin had increased from 9.7 g/dL to 11.6 g/dL and transfusion requirements were eliminated. Three patients, who had their hemoglobin levels increased with Hematide, improved sufficiently to undergo kidney transplant surgery. Hematide was generally well tolerated. Some adverse events, including bone pain, hypertension, injection site hematoma, and increased blood pressure, were considered possibly related to Hematide.

Hematide Phase 2 Trial Results Also Presented at ASN Conference

In addition to the oral presentation on PRCA trial results, two posters from two separate Phase 2 clinical trials of Hematide in dialysis and predialysis CKD patients were presented at the ASN conference. These data showed that Hematide increased hemoglobin in treatment-naive, predialysis patients when administered monthly at an appropriate dose. Similarly, the data in dialysis patients previously treated with three-times weekly Epoetin alfa demonstrated that mean hemoglobin levels were maintained at target levels following a switch to once-monthly dosing of Hematide at an appropriate dose.

About Hematide

Hematide is a novel synthetic, pegylated peptidic compound that binds to and activates the erythropoietin receptor and thus acts as an erythropoiesis stimulating agent. The investigational product is being evaluated in a Phase 3 program for the treatment of anemia in patients with dialysis and predialysis chronic renal failure (CRF) and earlier stage clinical trials in cancer patients receiving chemotherapy.

About PRCA

Dialysis and non-dialysis patients with CKD frequently develop anemia because of a reduction in native EPO production by dysfunctional kidneys. Since the late 1980s, recombinant EPO has been used successfully to treat anemia-associated EPO deficiency. A small number of CKD patients develop antibody-mediated PRCA, a type of anemia that develops when patients mount a neutralizing antibody response to recombinant EPO used to treat the anemia associated with CKD. These antibodies neutralize not only the recombinant EPO but also cross-neutralize natural EPO produced by the patients, leading to a state of absolute EPO resistance and transfusion dependence. While the incidence of PRCA has decreased, there continues to be sporadic reports of antibody-mediated PRCA associated with commercially available EPO products. Concern over PRCA prompted the addition of warnings in the prescribing information of all EPO-based products marketed in the U.S.

About Affymax, Inc.

Affymax, Inc. is a biopharmaceutical company developing novel drugs to improve the treatment of serious and often life-threatening conditions. Affymax’s lead product candidate, Hematide™, is currently in Phase 3 clinical trial stage for the treatment of anemia associated with chronic renal failure and in clinical trials for the treatment of anemia in cancer patients. For additional information, please visit www.affymax.com.

About Takeda

Located in Osaka, Japan, Takeda (TSE: 4502) is a research-based global company with its main focus on pharmaceuticals. As the largest pharmaceutical company in Japan and one of the global leaders of the industry, Takeda is committed to striving toward better health for individuals and progress in medicine by developing superior pharmaceutical products. Additional information about Takeda is available through its corporate website, www.takeda.com.

This release contains forward-looking statements, including statements regarding the timing, design and results of the Company’s clinical trials and drug development program and the timing and likelihood of the commercialization of Hematide. The Company’s actual results may differ materially from those indicated in these forward-looking statements due to risks and uncertainties, including risks relating to the continued safety and efficacy of Hematide in clinical development, the potential for once per month dosing, regulatory requirements and approvals, research and development efforts, industry and competitive environment, intellectual property rights and disputes and other matters that are described in the Company’s Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission. Investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date of this release. The Company undertakes no obligation to update any forward-looking statement in this press release.

A dog was referred to the Veterinary Teaching Hospital at the University of Georgia for the evaluation of severe anemia. The dog had a two-day history of lethargy and anorexia, and the referring veterinarian found a packed cell volume (PCV) of 14%.

On presentation, the patient's PCV was 19%, with macroscopic autoagglutination noted. A complete blood count the following day revealed a severe normocytic normochromic anemia with a hematocrit of 13.4%. A reticulocyte count was not performed. The hemogram also revealed a mild thrombocytopenia with many shift platelets, as well as a mild increase in the concentration of band neutrophils (although the total leukocyte and segmented neutrophil counts were within the reference range). A serum chemistry and urinalysis performed at the same time were largely unremarkable. Due to the severe anemia and autoagglutination, the patient was tentatively diagnosed with immune-mediated hemolytic anemia (IMHA). Immunosuppressive therapy was begun and the dog was transfused with 240mL of packed red blood cells. A subsequent reticulocyte count revealed a lack of regeneration. A bone marrow aspirate cytology indicated erythroid hyperplasia with maturation arrest and mild myeloid and megakaryocytic hyperplasia. Based on these findings, the patient was given a provisional diagnosis of pure red cell aplasia. This paper will explore how this preliminary diagnosis was re-evaluated.

PURE RED CELL APLASIA

Introduction

Pure red cell aplasia (PRCA) is a disorder in which anemia is caused by erythroid hypoplasia or aplasia, but without abnormalities in other hematopoietic cell lines.1 In truth, “aplasia” is probably an incorrect term, as the disease is thought to result from destruction of red blood cell precursors rather than a complete lack of erythropoiesis. Pure red cell aplasia has been reported in humans, dogs, and cats,1 although relatively few cases are present in the veterinary literature. The objective of this paper is to increase awareness of this disease, to emphasize the importance of appropriate diagnostic testing, and to summarize the disease process, diagnostic criteria, therapy and prognosis for patients with PRCA.

Normal Erythropoiesis

Production of a mature red blood cell requires three stages of differentiation and proliferation. The first stage involves the differentiation of a pluripotent stem cell into an erythroid progenitor cell known as a BFU-E. This step in the process occurs under the influence of several non-specific cytokines such as IL-3, GM-CSF, and stem-cell factor, which are produced by the cell’s microenvironment. BFU-Es then differentiate and proliferate into a second erythroid progenitor, the CFU-E, but only in the presence of erythropoietin, a renal hormone and growth factor. The final step in erythropoiesis involves production and maturation of nucleated red blood cell precursors, and proceeds automatically unless there is an absence of crucial factors such as proteins, iron, vitamin B12, or folic acid.2 In general, as an erythrocyte precursor becomes more mature, the cell size, nuclear-to-cytoplasm (N:C) ratio, and cytoplasmic basophilia all decrease.3

Pure red cell aplasia was first identified as a separate entity from aplastic anemia by Kaznelsen in 1922.2,4 PRCA has also been know as erythroblastic hypoplasia, erythroblastopenia, erythroid hypoplasia, and red cell agenesis.4 Pure red cell aplasia in humans can be separated into three forms: a congenital (constitutional) form, and two acquired forms that may be either 1) acute or 2) chronic.

The congenital form, also known as Diamond-Blackfan syndrome, is thought to be caused by some sort of prenatal injury or mutation.2 However, the effectiveness of steroid therapy in the disease has led to a search for an underlying immunologic cause.4 The acute, self-limiting form of PRCA has been most commonly associated with a viremia, and specifically with infection by the B19 parvovirus. In addition, numerous drugs and several nutritional deficiencies have been suspected of causing aplastic crises, although the link between nutritional deficiencies and aplasia is questionable. In any case, diagnosis of acute PRCA usually becomes evident from the patient’s clinical course, as recovery is usually already underway when the diagnosis is made.4

The chronic, acquired form of pure red cell aplasia has frequently been suspected of having an immune-mediated pathogenesis. An association between red cell aplasia and thymomas was noted in the 1930s.4 The mechanism was suspected to involve T lymphocyte-mediated destruction of erythroid cells,2 which has since been found to play a major role in the pathogenesis of the disease.4 However, many patients without thymomas were also diagnosed with chronic red cell aplasia. Some have suggested that two or more forms of the disease may exist, some of which may be associated with thymomas, and some which may have no connection.5 It appears that thymomas were more common in PRCA a generation ago than they are today,2 as a more recent case series showed only 2/37 red cell aplasias to be associated with thymomas.4 The chronic form of the disease has also been associated with other immune-mediated diseases such as rheumatoid arthritis, lupus erythematosus, chronic active hepatitis, hemolytic anemia, and chronic lymphatic leukemia.4 Chronic PRCA generally responds to treatment with blood transfusions and immunosuppressive agents, and the remission rate has been reported to be about 40% even with prednisone therapy alone.2

Pathogenesis: PRCA vs. NRIMA

True nonregenerative anemias result from several general causes:

bone marrow suppression secondary to chronic/inflammatory disease

infiltrative bone marrow disease (myelophthisis)

inadequate nutrients for erythropoiesis

immune-mediated destruction of erythroid progenitors in the bone marrow6

The complete pathogenesis of pure red cell aplasia is not completely known, but the disease can be either primary or secondary in nature. Secondary PRCA has been associated with parvovirus infection and treatment with recombinant human erythropoietin. Primary PRCA is believed to be a form of immune-mediated hemolytic anemia in which antibodies lead to destruction of erythroid precursor cells in the bone marrow.7 Most immune-mediated anemias are believed to be primary (idiopathic); however, this may reflect an inability to detect an underlying cause rather than true autoimmune disease.8

There is some overlap in the precise medical definitions of PRCA and non-regenerative immune-mediated anemia (NRIMA). Some define pure red cell aplasia as complete arrest of the erythroid cell line at any stage of maturation. However, most6,7 agree that a patient qualifies as having pure red cell aplasia only if bone marrow samples are devoid of, or nearly completely lacking in, all red cell precursors. Those in the latter group tend to refer to immune-mediated destruction of later-stage precursors as “nonregenerative immune-mediated anemia (NRIMA),” and believe that PRCA is the most severe or end-stage expression of NRIMA.6 Using the most favored definition of pure red cell aplasia, the patient presented at the beginning of this paper should have been diagnosed not with PRCA, but with NRIMA.

Regardless of whether or not one separates pure red cell aplasia from nonregenerative immune-mediated anemia, it appears as though antibody-mediated immune destruction of erythrocyte precursors is a key mechanism of both manifestations of the disease. Typically, in normal animals, suppressor T lymphocytes prevent reaction of autoantibodies with host tissues. However, as is thought to be the case in humans, animals with immune-mediated anemias may have defective suppressor T cell function or hyperfunctioning immune systems. These characteristics may suggest a genetic predisposition to the development of these conditions.8

The exact antigen(s) to which the antibodies react in nonregenerative immune-mediated anemias is unknown, but late-stage erythroid precursors (metarubricytes and even reticulocytes) appear to be targeted in many dogs, while true PRCA is very uncommon. In some cases, the attack may be aimed at a maturation-associated antigen, which leads to destruction only of erythroid precursors. However, some antigens are common on both precursors and mature red blood cells, so it is possible that destruction of both stages may occur if a common antigen is targeted. Additionally, some patients have developed immune-mediated thrombocytopenia following successful treatment of this disease, indicating that they may have had a more generalized immune-mediated reaction.6 It is possible that the patient described in this paper may have been suffering from a more generalized immune attack involving both red blood cells and platelets as targets of immune destruction.

Signalment, History, and Clinical Signs

Immune-mediated anemias are much more common in dogs than in cats,8 although there is a report of pure red cell aplasia in 9 cats between 8 months and 3 years of age, all of whom tested seronegative for retroviruses (FeLV/FIV).9 Middle-aged female dogs tend to be overrepresented,6-8 as is the case with many immune-mediated diseases. Two studies of PRCA and NRIMA have shown a significant overrepresentation of Labrador Retrievers when compared to overall hospital population, indicating that the breed may somehow be predisposed to developing this disorder. Interestingly, breeds commonly affected by immune-mediated hemolytic anemia (Cocker Spaniels, Old English Sheepdogs, Irish Setters, Poodles, English Springer Spaniels, and Collies) do not appear to be at increased risk for development of PRCA.6

Patients with pure red cell aplasia may present to the veterinarian with a relatively nonspecific history and very few clinical signs. This may result from the chronicity of the disease and the ability of the body to compensate for a slowly progressive anemia. Owners may report simply that their pets are lethargic and/or anorexic, with few other presenting complaints. Patients may also have a history of pallor, weakness, exercise intolerance, weight loss, and collapse.6,7

Physical exam commonly reveals pale mucous membranes and tachypnea, and possibly hepatomegaly and splenomegaly.6,7 Cardiovascular changes are common in severely anemic (PCV < 20%) patients, and may include tachycardia, gallop rhythm, and a grade II-III/VI systolic heart murmur. The systolic murmur heard in anemic patients is due to abnormal blood turbulence8 rather than a true cardiac abnormality. If a patient has a more generalized immune-mediated anemia that also affects circulating red blood cells, icterus may be seen in addition to the previously mentioned abnormalities due to marked destruction of red blood cells and increased bilirubin metabolism.

Diagnostic Findings

Complete Blood Count / Serum Chemistry / Urinalysis: The most readily obvious laboratory abnormality in a patient with pure red cell aplasia is a nonregenerative anemia. The anemia can be severe, and is typically normocytic and normochromic with occasional spherocytosis.1 The patient may be positive on a Coombs’ (direct antiglobulin) test1 depending on the antigen targeted by the immune attack. Serum chemistry and urinalysis are unremarkable in many patients. The most common biochemical abnormalities reported are increased liver enzyme activities (possibly due to hypoxia, corticosteroid administration, and cholestasis), low bicarbonate concentration (due to hypoxia and subsequent lactic acidosis), and hyperferremia (due to lysis of red blood cells).6 However, these findings are inconsistent between patients. Additionally, if an antigen that is common to erythroid precursors and mature RBCs is targeted, evidence of peripheral red cell lysis may rarely be seen (hemoglobinemia/hemoglobinuria, hyperbilirubinemia/bilirubinuria, etc.).

Thoracic and Abdominal Imaging: Observations may include mild hepatomegaly or splenomegaly, but radiographic and ultrasonographic exams generally detect few to no abnormalities.

Bone Marrow: It is not possible to predict the condition of the bone marrow from hematologic findings alone. Hemogram results in patients with pure red cell aplasia can appear very similar to findings in patients with erythroid hyperplasia.6 Therefore, it is very important to obtain bone marrow aspirates in patients with nonregenerative anemias. In one study of 13 dogs with pure red cell aplasia,7 the marrow of 9 dogs contained no erythroid cells, while rare rubriblasts and prorubricytes were seen in 4 dogs. Another study of PRCA and NRIMA6 found erythroid hypoplasia in 11/42 dogs (26%) and no erythroid precursors in 2/42 dogs (5%). Myelofibrosis has been reported to occur in dogs with immune-mediated anemias, which can make it difficult to obtain bone marrow samples. Patients with more generalized attack on erythroid cells may develop some fibrosis over time secondary to immune-mediated destruction of red cell precursors; however, in both studies cited here,6,7 bone marrow core biopsies revealed no collagen fibrosis in patients with complete absence of erythroid precursors in the bone marrow (PRCA).

Figures 2A and 2B. Normal bone marrow (A, left) and bone marrow from the patient described in this paper (B, right). The patient’s erythroid series consists almost exclusively of high numbers of rubriblasts and prorubricytes. A few rubricytes are seen, but later stage precursors are virtually absent. These findings are consistent with a diagnosis of nonregenerative immune-mediated anemia. No bone marrow slides were available from a patient with pure red cell aplasia, and a search of medical records did not indicate that a patient with PRCA has been seen recently at the University of Georgia.

Treatment

Note: Treatment of animals should only be performed by a licensed veterinarian. Veterinarians should consult the current literature and current pharmacological formularies before initiating any treatment protocol.

Treatment for pure red cell aplasia and nonregenerative immune-mediated anemias is multimodal, and is often similar to treatment for peripheral forms of immune-mediated hemolytic anemia. As PRCA is believed to be an immune-mediated disease, one of the major aspects of treatment involves immunosuppression. A variety of immunosuppressive drugs are now available. Corticosteroids (for example, prednisone and dexamethasone) have been the mainstay of immunosuppressive therapy for quite some time. They are relatively inexpensive, fast-acting, and fairly efficacious. However, long-term immunosuppressive doses of corticosteroids are known to produce several undesirable side effects (iatrogenic Cushings disease), so additional drugs are often utilized to allow the clinician to taper the dose of steroids over time. Two commonly used, additional immunosuppressive agents are the T cell inhibitors, azathioprine and cyclosporine. In addition to immunosuppressive therapy, patients with immune-mediated anemias require a significant amount of supportive care, such as blood transfusions.

Prognosis

The prognosis for patients with PRCA and nonregenerative immune-mediated anemia was once believed to be much poorer than the prognosis for patients with regenerative immune-mediated anemias. However, recent data indicates that the prognosis for NRIMA may be equivalent to or better than regenerative IMA, and the long-term prognosis for PRCA may even be better than the prognosis for other NRIMA.7

In one retrospective study7 of 13 PRCA dogs treated with prednisolone /- cyclophosphamide, 10 dogs had complete remission of anemia, and 1 dog had partial remission. The other two dogs were euthanized within four weeks after treatment was initiated, and it is unknown whether they would have also responded if given more time. For dogs that did respond to treatment, the median initial response time (response defined as a 5% increase in hematocrit) was 38 days (range 22-87 days), and the median time for complete remission (defined as a normal Hct) was 118 days (range 58-187 days). Another study6 examined dogs with PRCA and NRIMA treated with various combinations of corticosteroids, cyclophosphamide, and azathioprine. In this study, 55% of dogs had a complete response to therapy, 18% had a partial response, and 27% had no response. For those who responded, initial response was seen at a median of 2 weeks (range 1-10 weeks), and remission was seen within 1-10 months after the start of treatment.

Mortality statistics obviously vary between studies, but is has been reported that in dogs with regenerative immune-mediated anemia, the mortality rate is approximately 29%, while in dogs with nonregenerative immune-mediated anemia, the mortality rate is 28%.7 This may result because patients with regenerative IMA do not typically die from the anemia itself.10 More commonly, they die from hemolysis-associated activation of the coagulation system, which leads to disseminated intravascular coagulopathy (DIC) or pulmonary thromboembolism (PTE).7 Peripheral hemolysis is not as common in patients with PRCA and NRIMA, so they do not commonly suffer from DIC or PTE. Therefore, patients with PRCA and NRIMA may actually have a better long-term prognosis than patients with regenerative IMA if given time to respond to therapy.

Summary

Pure red cell aplasia is a rare disorder in veterinary medicine in which anemia is caused by erythroid hypoplasia or aplasia, but other hematopoietic cell lines are not defective. The disease may sometimes be confused with nonregenerative immune-mediated anemia (NRIMA), but the strict definition of PRCA requires a complete (or nearly complete) absence of all erythroid precursors in the bone marrow. PRCA is believed to be the most severe, end-stage manifestation of NRIMA. The pathogenesis is not completely understood, but is thought to involve antibody-mediated destruction of red cell precursors. Antibodies may be directed against a maturation-associated antigen, or against an antigen that is common to both precursors and mature red blood cells. PRCA has been reported in humans, dogs, and cats. Patients commonly present for nonspecific signs such as lethargy and anorexia, and initial blood work shows a nonregenerative anemia. There may or may not be additional clinical signs and laboratory abnormalities. As hemogram results can be similar for PRCA and other causes of nonregenerative anemia, bone marrow sampling is essential for appropriate diagnosis. As PRCA is believed to be immune-mediated, treatment consists mainly of immunosuppression and supportive care (including blood transfusions as necessary). The prognosis in PRCA and other nonregenerative immune-mediated anemias is guarded, but may be better than the prognosis for regenerative immune-mediated anemias (such as the more classic peripheral form of IMHA) if patients are given an appropriate amount of time to respond to therapy.

The images of the bone marrow needles, transfusion items, and the photomicrographs of the bone marrow aspirates were obtained by the primary author (MK) with permission. A big thank you goes to Dr. Tripp Almy for the erythropoiesis images, as well as the members of the Clinical Pathology and Internal Medicine services at the UGA College of Veterinary Medicine for their help with this paper and for assisting with my understanding of this disease process and case.

Paul Schick, MD, is a member of the following medical societies: American Association for the Advancement of Science, American College of Physicians, American Heart Association, American Society of Hematology, International Society on Thrombosis and Haemostasis, and New York Academy of Sciences

Background: Pure red cell aplasia (PRCA) describes a condition in which there is a near absence of red blood cell precursors in bone marrow, while megakaryocytes and white blood cell precursors usually are present at normal levels. In 1922, Kaznelson recognized that this condition was a different entity than aplastic anemia. PRCA exists in several forms, and the most common form is an acute self-limiting condition. Acquired PRCA often is chronic and is associated with underlying disorders such as thymomas and autoimmune diseases. A congenital form of PRCA initially was described by Joseph in 1936 and by Diamond-Blackfan in 1938. Congenital PRCA is a lifelong disorder, and it is associated with physical abnormalities. Both acquired and congenital PRCA occasionally can be refractory to therapy.

Pathophysiology: Erythroid precursors in bone marrow are the primary targets in PRCA. As a result, patient can develop a normoblastic normochromic anemia and a virtual absence of reticulocytes.

Injury of stem cells in utero is believed to be the etiology of approximately 90% of cases of congenital PRCA (ie, Diamond-Blackfan syndrome). This therapy is based on evidence that congenital PRCA frequently is associated with random physical abnormalities, while it rarely is familial or associated with significant chromosomal abnormalities. However, a familial history of PRCA has been detected in approximately 10% of patients with the congenital form of PRCA.

The acute self-limited form is secondary to viral and drug-induced impairment of erythroid progenitor cells. The acquired chronic form of PRCA is associated with thymomas and autoimmune disorders. Damage to erythroid progenitors or precursor cells appears to be immune and T-cell mediated. In both the acute and acquired chronic forms of PRCA, the affected cells are progenitors that have differentiated from stem cells and can express erythropoietin receptors. Thus, unlike in congenital PRCA, stem cells usually are not the targets in the acute and acquired forms of PRCA.

Frequency:

In the US: Acute transient PRCA is the most common form of PRCA. However, its incidence most likely has been underestimated because viral and drug-induced PRCA aplasias usually are self-limiting, and patients generally do not seek medical attention.

Since 1936, when this disorder was originally reported, hundreds of cases of congenital PRCA have been reported.

Mortality/Morbidity: Since most cases of PRCA are the acute self-limiting form of PRCA, the incidence of morbidity and mortality in PRCA is not significant. The mortality rate in acquired chronic PRCA and in congenital PRCA is expected to be slightly greater than in the acute form of PRCA. Most individuals with congenital PRCA survive to early adulthood.

When acquired PRCA is associated with thymomas and autoimmune disorders, morbidity can be due to these underlying conditions. Patients with the congenital form of PRCA also can have physical abnormalities.

Profound transfusion-dependent anemia is the most common morbidity of acquired chronic PRCA and congenital PRCA. However, the treatment of anemia in PRCA can contribute to significant morbidity, as follows:

Transfusion therapy can lead to hemosiderosis, and the consequences of iron overload are growth retardation, delay in sexual maturity, cardiac arrhythmias, and cardiac failure. Transfusions also can transmit infections.

Corticosteroid therapy can lead to growth retardation, osteopenia, diabetes, and other complications.

Because of immunotherapy, a small percentage of patients can develop aplastic anemia or acute myelogenous leukemia, and both conditions have high morbidity and mortality rates.

Race: No racial preponderance is observed.

Sex: Females are more likely to be affected in immunologically related PRCA. However, the male-to-female ratio is 2:1 for PRCA associated with thymoma. CLINICAL Section 3 of 9

History: Anemia is the primary problem in PRCA. The degree of anemia can range from subclinical to severe. Anemia in acute self-limiting PRCA is barely noticeable. Profound anemias also can occur in chronic acquired PRCA and in congenital PRCA. Patients with severe anemias have symptoms and signs of uncompensated anemia and present with weakness, tachycardia, and dyspnea.

Acute self-limiting PRCA due to viral infections

Often, the patient has a recent history of infectious diseases such as respiratory illnesses or gastroenteritis.

Mumps, infectious mononucleosis, and viral hepatitis often precede the development of acute PRCA. Symptoms ascribable to these infectious processes may predominate over those of the transient anemia.

Since the decrease in the hemoglobin (Hgb) level is gradual and self-limited, most cases of acute PRCA often are unnoticed.

In patients with acute PRCA who have hemolytic disorders, anemia can be severe because there is virtually no production of erythrocytes to compensate for hemolysis. This is known as an aplastic crisis. Under these conditions, patients can develop uncompensated anemia with marked weakness and dyspnea.

Acute self-limiting PRCA due to drugs

Patients may have a history of taking drugs that can induce PCRA.

Having taken a medication for an extended period does not rule out the possibility that the drug is responsible for the episode of acute PCRA.

See Causes for a list of medications reported to cause PRCA.

In some cases of acute PRCA due to viral infections or drugs, PRCA may persist for a prolonged period. Several explanations are proposed for this chronicity.

Patients who are immunocompromised cannot mount an adequate defense against viral infections.

Some individuals have an underlying sensitivity to drugs that can induce PRCA.

In other patients, an underlying subclinical disorder predisposes patients to prolonged PRCA. The acute PRCA superimposed on an underlying condition can be severe and prolonged.

A careful history should be taken to elucidate conditions that could lead to this chronicity.

Acquired chronic (ie, sustained) PRCA

In addition to evidence of anemia, the history may suggest an underlying thymoma, lymphoproliferative disorders, systemic lupus erythematosus (SLE), autoimmune disorders, or immunocompromised states.

Autoimmune disorders may be associated with arthritis.

Thymomas rarely are large enough to be detected during the physical examination.

Lymphadenopathy and splenomegaly may indicate the presence of an underlying lymphoproliferative disorder or SLE.

Congenital PRCA

Some, but not all, cases of congenital PRCA are associated with severe anemias.

In addition to anemia, approximately one third of patients develop with physical abnormalities, most often involving the head, upper limbs, thumbs, the urogenital system, or the cardiovascular system. Growth retardation and unusual thumb formation can occur. However, these physical deformities are less severe than in Fanconi syndrome.

Anemia often is not observed during the early neonatal period, but pallor, weakness, and dyspnea attributable to the anemia develop during the first year of life.

Physical: The signs of anemia and its severity are the major physical findings in PRCA. Pallor and weakness are early manifestations. Evidence of a decompensated anemia (eg, dyspnea, tachycardia, incipient heart failure) occurs in more severe anemias. Severe anemias can be observed in patients with acute PRCA and hemolytic disorders who develop an aplastic crisis. Specific physical findings in acute, acquired chronic, and congenital PRCA are described below:

Acute self-limited PRCA

Often, physical evidence of anemia is scant or borderline.

Evidence of a recent viral infection (eg, a rash, jaundice in viral hepatitis, splenomegaly in infectious mononucleosis, enlarged parotid glands in mumps) may be present.

When acute PRCA occurs in patients with hemolytic anemias, physical evidence of the hemolytic disorder (eg, splenomegaly, leg ulcers) may be present.

Acquired chronic (ie, sustained) PRCA

In addition to evidence of anemia, the potential exists for detecting physical findings of underlying thymomas, lymphoproliferative disorders, autoimmune disorders, or immunocompromised states. However, thymomas rarely are large enough to be detected by the physical examination.

Lymphadenopathy and splenomegaly may indicate the presence of an underlying lymphoproliferative disorder.

Congenital chronic PRCA (ie, Diamond-Blackfan syndrome)

The severity of the anemia varies among patient populations.

Anemia often is not recognized during the early neonatal period but usually is apparent during the first 2 years of life.

More than one third of patients have malformations or mental retardation.

Osteogenic carcinoma of the mandible and abnormalities of the thumbs have been observed.

In general, these physical abnormalities are not as severe as those observed in Fanconi syndrome. Thymomas have not been found in these patients.

Complications of therapy may be evident on the physical examination.

Iron overload secondary to transfusion therapy can present as hyperpigmentation of the skin, arthralgias, cardiac arrhythmia, evidence of endocrinopathies, jaundice due to hepatic dysfunction, and hepatosplenomegaly.

Complications of corticosteroid therapy include retarded growth, diabetes, and osteopenia.

Complications of immunotherapy can include aplastic anemia and an acute myelogenous leukemia. Physical findings due to these complications of therapy may be evident on physical examination.

Causes: The etiology of PRCA is diverse and differs in acute self-limited, acquired chronic (sustained), and congenital chronic forms of PRCA.

Acute self-limited PRCA can be caused by viral infections or certain medications.

Most cases of acute transient PRCA are caused by parvovirus B19 infection. Parvovirus B19 can cross the placenta in infected women and can destroy erythroid cells in the fetus; in some cases, the virus can induce spontaneous abortion.

Medications: Most drugs are believed to cause PRCA by exerting a direct toxic effect on red blood cell precursors. The evidence for drug-induced immunological selective impairment of red cell production is controversial.

Thymomas: Originally, thymoma was cited as the primary cause of acquired PRCA. However, subsequent studies revealed that thymoma caused only 2 of 37 cases of PRCA. Conversely, only 7% of patients with thymomas had PRCA. T-cell–mediated erythroid rejection is considered the mechanism for the production of PRCA in patients with thymomas. This is supported by evidence that a subgroup of T cells in B-cell chronic lymphocytic leukemia is responsible for PRCA.

Autoimmune disorders: PRCA has been associated with rheumatoid arthritis, SLE, autoimmune hemolytic anemia, chronic active hepatitis, collagen vascular diseases, and chronic lymphocytic leukemia. Immunoglobulin G (IgG) antibodies in sera from many of these patients suppressed the growth of red cell precursors. Evidence exists that, in some cases, acquired chronic PRCA can be T cell mediated. The occurrence and role of autoimmune antibodies against erythropoietin in PRCA have not been substantiated.

Patients who are immunocompromised: PRCA occurs in these patients and may be due to the persistent parvovirus B19 infections. In healthy persons, an IgG and immunoglobulin M (IgM) response limits the parvovirus infection, but this response is attenuated in individuals who are immunocompromised.

The etiology of congenital chronic PRCA (ie, Diamond-Blackfan syndrome) is not clear.

Approximately 90% of cases are sporadic, and it has been suggested that the sporadic cases are caused by in utero damage to erythroid stem cells. This theory is based on evidence that, while the Diamond-Blackfan syndrome frequently presents with random physical abnormalities, it rarely is familial or associated with significant chromosomal abnormalities.

In 10% of patients, a dominant or, more rarely, recessive familial pattern has been observed. One locus on chromosome 19q13.2 encoding ribosomal protein S19 accounts for a quarter of patients with either the dominant or the sporadic form. Families that are not linked with this locus also have been described.

WORKUP Section 4 of 9

Lab Studies:

Basic studies

CBC

Platelet count

Differential count

RBC indices

Reticulocyte count

Studies to rule out hemolysis

Lactate dehydrogenase (LDH)

Indirect bilirubin

Serum haptoglobin

Studies to rule out iron overload

Serum iron

Total iron-binding capacity (TIBC)

Serum ferritin levels

In some cases, liver biopsy with quantitation of iron levels may be indicated.

In acute PRCA, rule out the following:

Parvovirus B19

Infectious mononucleosis

Atypical mycoplasmic pneumonia

Mumps

Viral hepatitis

In acquired chronic PRCA, rule out the following:

Human immunodeficiency virus

Thymoma

Chronic active hepatitis

Systemic lupus erythematosus

Autoimmune disorders (direct Coombs test)

Collagen vascular disorders

Pregnancy

Congenital PRCA

Fetal Hgb and erythrocyte adenine deaminase (ADA)

Serum folate and vitamin B-12

Genetic testing

Megaloblastic changes can be observed on peripheral smears.

Imaging Studies:

Chest x-ray (posteroanterior and lateral)

Computerized tomography to rule out a thymoma

Magnetic resonance imaging to rule out thymoma

Procedures:

Bone marrow aspiration and biopsy are indicated to confirm the diagnosis. This procedure may not be indicated in acute PRCA. Bone marrow biopsy may be useful to assess iron overload. A bone marrow biopsy is indicated to diagnose an acute myelogenous leukemia, which can be a complication of immunotherapy.

Histologic Findings: Bone marrow aspirates and biopsy usually reveal a selective depletion in RBC precursors. In congential PRCA, megaloblastosis of RBC precursors may be observed, and, occasionally, there is a depression in the level of megakaryocyte and WBC precursors.

In acute PRCA, a bone marrow aspiration and biopsy performed during the recovery phase may be misleading and may suggest active erythropoiesis.

Biopsy of a thymoma usually reveals that the tumor is encapsulated and contains primarily spindle cells, with or without small lymphocytes.

TREATMENT Section 5 of 9

Medical Care: Specific aspects of the treatment of acute, chronic acquired, and congenital forms of PRCA are mentioned below. Common to all forms is the treatment of anemia. Adequate Hgb levels should be maintained by transfusion therapy. Folic acid and multivitamins have been recommended, but their value has not been established. High-dose immunoglobin can be used to transiently restore Hgb levels in parvovirus B19 infections and other forms of acquired PRCA.

The decision to hospitalize patients with PRCA or to treat them in an outpatient setting depends on their clinical status and the ability to evaluate, treat, and transfuse patients outside the hospital setting.

Acute self-limiting PRCA

Discontinue offending drugs and treatment of associated infections or other illness.

Transfusion therapy usually is not indicated because of the self-limiting nature of acute PRCA.

Transfusions may be indicated in patients with hemolytic anemias who develop PRCA.

Corticosteroids can be effective, but a high dosage often is required, and the adverse effects frequently preclude using these agents. However, some patients respond to low doses of corticosteroids. Prednisone can induce remission in approximately 45% of cases.

If the underlying cause of PRCA is immunological and the response to corticosteroids has been inadequate, the next level of treatment is with cytotoxic or immunosuppressive drugs. The following agents have been used: (1) cyclophosphamide, (2) 6-mercaptopurine, (3) azathioprine, or (4) cyclosporine, at sufficient dosage to induce leukopenia, have been effective. Some immunogenic agents can be leukemogenic.

Antithymic or antilymphocyte serum has been effective. Several patients have responded to plasmapheresis or lymphocytapheresis.

Patients who are refractory to immunosuppressive therapy may respond to Danazol.

Transfusions most likely have to be performed on a weekly basis to maintain an adequate Hgb level as long as patients do not respond to any of the above measures. Two units of blood every 2 weeks usually are sufficient, unless patients have hypersplenism, blood loss, or hemolysis. Consider iron chelation in patients with a prolonged transfusion requirement to avoid hemosiderosis.

Congenital PRCA

Treatment is complicated because this condition is a lifelong disorder, and the consequences of treatment can have devastating effects on growth and sexual maturity.

Transfusion is an integral modality in treating congential PRCA. The severity of anemia varies from patient to patient. With severe anemia, patients can have a lifelong dependency on transfusions. Two units of blood every 2 weeks usually are sufficient. Aggressive chelation using deferrioxamine (ie, desferrioxamine) infusions are critical to avoid hemosiderosis because transfusion therapy usually is started at a young age.

Corticosteroids also are a principal therapeutic option, and this therapy is believed to allow the abnormal stem cells in congenital PRCA to become more sensitive to growth factors. High doses of prednisone (1-2 mg/kg) are needed but should not be continued for more than 4-6 weeks. Following a failure in prednisone therapy, a trial of high-dose methylprednisolone can be tried. Some patients respond to high-dose corticosteroid therapy and can be maintained on low doses of these agents. The major complications of corticosteroid therapy in these patients are growth retardation, muscle weakness, and osteopenia.

Cyclosporine has been used but has not been effective. Danazol and other androgens can be used in refractory cases, but these agents may be contraindicated in prepubertal children.

Bone marrow transplantation has been used and could be considered in patients who are refractory and who have human leukocyte antigen (HLA)-identical siblings.

Surgical Care: Surgical are may be indicated if a thymoma is suspected or if the patient has significant hypersplenism.

Thymectomy

This procedure may be indicated for the treatment of acquired chronic PRCA. However, the incidence of thymoma-induced PRCA is not as common as it had been reported in the past.

Recent evidence indicates that only 30% of patients with acquired PRCA responded to thymectomy, and that only 2 of 37 patients with PRCA had thymic enlargement.

While the removal of a thymoma may be helpful, the removal of a normal thymus has not been effective in treating PRCA.

Splenectomy is not indicated unless hypersplenism can be documented to interfere with the treatment of PRCA.

Consultations: Consulting a hematologist and rheumatologist may be indicated.

Consult a hematologist to assist with the treatment of patients with hypersplenism, underlying hemolytic anemia, and the underlying lymphoproliferative disorders. A hematologist should be consulted to monitor therapy, especially immunotherapy, intravenous IgG and ATG therapy.

Consult a rheumatologist or a specialist in collagen vascular diseases if rheumatoid or collagen vascular disorders may be responsible for PRCA.

Activity: Activity should be monitored and, at times, curtailed in patients with significant anemia. MEDICATION Section 6 of 9

The goal of therapy is to restore erythroid production, to maintain the Hgb at an adequate level, and to treat underlying disorders. Therapy also is designed to prevent and treat complications of therapy.

Drug Category: Corticosteroids -- Mainstay of therapy for PRCA. Approximately 45% of patients with PRCA respond to corticosteroids.Drug Name

Prednisone (Deltasone, Orasone, Meticorten) -- These agents are useful in acquired PRCA because they can modify the body's immune response. In congenital PRCA, corticosteroids are believed to allow the abnormal stem cells to become more sensitive to growth factors. These agents have an anti-inflammatory effect, have a profound effect on metabolism, and have a number of potentially serious adverse effects.

Refer to references listed in bibliography for a complete list of potential contraindications. The benefits and risks of corticosteroids should be individualized in treating PRCA.

Drug Category: Immunosuppressive agents -- Important agents for the treatment of PRCA. Cytoxan, 6-mercaptopurine and azathioprine are used most often. Has been reported that cyclosporine has not been effective. These agents increase the remission rate and may reduce the dose of corticosteroids needed to manage PRCA. Typical doses for immunosuppressive agents are listed below. A hematologist should be consulted to individualize the doses of immunosuppressive agents to arrive at the appropriate dosage.

Antilymphocytic serum and high-dose IVIG. These therapies need to be administered by physicians with extensive experience with these agents since there are a number of complications that should be anticipated and monitored.

Androgens (danazol) may be effective in some cases of refractory PRCADrug Name

Cyclophosphamide (Cytoxan, Neosar) -- Chemically related to nitrogen mustards. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.

Chloramphenicol may increase half-life while decreasing metabolite concentrations; may increase effect of anticoagulants; coadministration with high doses of phenobarbital may increase rate of metabolism and leukopenic activity; thiazide diuretics may prolong cyclophosphamide-induced leukopenia and neuromuscular blockade by inhibiting cholinesterase activity

Pregnancy D - Unsafe in pregnancy

Precautions Regularly examine hematologic profile (particularly neutrophils and platelets) to monitor for hematopoietic suppression; nausea and vomiting may occur; reversible hair loss may occur; regularly examine urine for RBCs, which may precede hemorrhagic cystitis; hydration (2-3 quarts of fluid daily) may prevent development of hemorrhagic cystitis; patients should be monitored for the development of Cytoxan-related acute leukemia and myelodysplastic syndromes

Pregnancy C - Safety for use during pregnancy has not been established.

Precautions Evaluate renal and liver functions often by measuring BUN, serum creatinine, serum bilirubin and liver enzymes; may increase risk of infection and lymphoma; reserve IV use only for those who cannot take PO

Drug Name

Antithymocyte globulin (Thymoglobulin) -- Purified concentrated gamma-globulin (primarily monomeric IgG) from hyperimmune horses immunized with human thymic lymphocytes. Mechanism of action is thought to be its effect on lymphocytes responsible in part on for cell-mediated immunity and lymphocytes involved in cell immunity.

A hematologist or another physician with extensive experience must be involved in the administration and monitoring of antilymphocyte serum because of the many complications and side effects of this therapy.

Adult Dose 10-20 mg/kg/d IV for 8-14 d; a test dose of 5 mcg IM should be given and anaphylaxis monitored

Pediatric Dose Not established

Contraindications Documented hypersensitivity; severe thrombocytopenia, leukopenia, or aplastic anemia; anaphylaxis; should not be given to a patient who has received varicella vaccine or another live vaccine within 3 mo

Interactions Unstable in acidic solutions and will precipitate when in dextrose solutions (package inserts describe optimal)

Pregnancy C - Safety for use during pregnancy has not been established.

Intravenous immune globulin (Gammaimmune, Gammagard, Sandoglobulin, Gammar-P) -- A hematologist or a physician experienced in administering this agent should be consulted because anaphylaxis, renal failure, transmission of infections, and aseptic meningitis are potential complications of this therapy. Experience in selecting patients that can tolerate IVIG, dosage, monitoring for adverse effects and managing complication of therapy are mandatory. One has also to consider the expense of this therapy.

Total dose is given IV but is graduated with low doses initially to monitor for anaphylaxis and other complications. Therefore, doses mentioned in package insert should be followed. Lower dosages per day but extended over 4 days are indicated in patients with fluid overload.

The goals are to complete the workup, initiate appropriate treatments, monitor the response to therapy, and manage potential adverse effects of therapy.

Response to therapy: An increase in the reticulocyte count is the earliest response to therapy or evidence of a spontaneous remission. Subsequently, a rise in Hgb to normal levels is expected. If there is a partial response, consider other causes of anemia (eg, iron deficiency, blood loss, hemolysis, chronic disease).

Acquired chronic PRCA is associated with a number of complications. The morbidity depends on the underlying conditions, the response to therapy, and the complications of therapy. Mortality is low.

Congenital PRCA usually is a lifelong disorder and is associated with a high morbidity rate due to the disorder and the treatment of the condition. Most patients survive through early adulthood, and estimating the mortality in this disorder has been difficult.

Patient Education:

The consequences of iron overload due to repeated transfusions should be explained to patients and to responsible parents if the patient is a child. This is important because hemosiderosis may cause growth failure and the retardation of sexual development.

The possibility of the transmission of infections by transfusion therapy, intravenous IgG and antilymphocytic serum should be explained.

The diverse adverse effects of corticosteroids, immunotherapy, and other aspects of managements should be explained.

MISCELLANEOUS Section 8 of 9

Medical/Legal Pitfalls:

Missing the diagnosis or instituting inappropriate care is subject to lawsuits. However, a few points should be considered, as follows:

Failure to explain the consequences of iron overload due to transfusions

Failure to explain the possibility of transmission of infections by transfusion, intravenous IgG, and antilymphocytic therapy.

Failure to explain the adverse effects of corticosteroids, immunotherapy, and other aspects of treatment

The administration of immunotherapy, intravenous IgG and antilymphocytic therapy without consultation and significant involvement of a physician with extensive experience with these agents.

Pure red cell aplasia (PRCA) describes a condition in which RBC precursors in bone marrow are nearly absent, while megakaryocytes and WBC precursors are usually present at normal levels. In 1922, Kaznelson recognized that this condition was a different entity than aplastic anemia. Pure red cell aplasia exists in several forms, and the most common form is an acute self-limited condition. Acquired pure red cell aplasia is often chronic and is associated with underlying disorders such as thymomas and autoimmune diseases. A congenital form of pure red cell aplasia was initially described by Joseph in 1936 and by Diamond-Blackfan in 1938. Congenital pure red cell aplasia is a lifelong disorder, and it is associated with physical abnormalities. Both acquired and congenital pure red cell aplasia are occasionally refractory to therapy.

Recent research

Because PRCA is one of the autoimmune diseases observed in patients with lymphoma, Hirokawa et al attempted to discern the relationship between the 2 conditions,1 assessing the disease characteristics in 8 patients who had both of these disorders. Half of the patients were found to have B-cell lymphoma, and the rest of them had the T-cell type. In 4 patients, PRCA and lymphoma developed simultaneously; in 3 of them, PRCA developed after the appearance of lymphoma (with 2 of these patients developing anemia while their lymphoma was in remission); and in 1 patient, PRCA developed first.

Chemotherapy and/or immunosuppressive therapy proved to be effective against anemia in 7 patients, with PRCA remaining in durable remission in 4 of these individuals without the use of maintenance immunosuppressive therapy. Based on their results, the authors suggested that lymphoma-associated PRCA is linked to a heterogeneous mechanism.

Pathophysiology

Erythroid precursors in bone marrow are the primary targets in pure red cell aplasia. As a result, patients can develop a normoblastic normochromic anemia and a virtual absence of reticulocytes.

Injury to stem cells in utero is believed to be the etiology of approximately 90% of cases of congenital pure red cell aplasia (ie, Diamond-Blackfan syndrome).2 This theory is based on evidence that congenital pure red cell aplasia is frequently associated with random physical abnormalities, while it is rarely familial or associated with significant chromosomal abnormalities. However, a familial history of pure red cell aplasia has been detected in approximately 10% of patients with the congenital form of pure red cell aplasia.

The acute self-limited form is secondary to virus- and drug-induced impairment of erythroid progenitor cells. The acquired chronic form of pure red cell aplasia is associated with thymomas3 and autoimmune disorders. Damage to erythroid progenitors or precursor cells appears to be immune and T-cell mediated. In both the acute and acquired chronic forms of pure red cell aplasia, the affected cells are progenitors that have differentiated from stem cells and can express erythropoietin (EPO) receptors. Thus, unlike in congenital pure red cell aplasia, stem cells are not usually the targets in the acute and acquired forms of pure red cell aplasia.

Interestingly, pure red cell aplasia can be induced by FeLV-C/Sarma, a feline retrovirus, and this has been proposed as a model system for studying pure red cell aplasia. Additionally, dogs can develop pure red cell aplasia that responds readily to immunosuppressive therapy.

Frequency

United States

Acute transient pure red cell aplasia is the most common form of pure red cell aplasia. However, its frequency has most likely been underestimated because virus- and drug-induced pure red cell aplasias are usually self-limited and patients generally do not seek medical attention. Acquired forms associated with thymomas and autoimmune disorders are relatively uncommon. Since 1936, when this disorder was originally reported, hundreds of cases of congenital pure red cell aplasia have been reported.

Mortality/Morbidity

Because most cases of pure red cell aplasia are the acute self-limited form of pure red cell aplasia, morbidity and mortality from pure red cell aplasia are not significant. The mortality rate for acquired chronic pure red cell aplasia and for congenital pure red cell aplasia is expected to be slightly greater than that for the acute form of pure red cell aplasia. Most individuals with congenital pure red cell aplasia survive to early adulthood.

When acquired pure red cell aplasia is associated with thymomas and autoimmune disorders, morbidity can be due to these underlying conditions. Patients with the congenital form of pure red cell aplasia can also have physical abnormalities.

Profound transfusion-dependent anemia is the most common morbidity associated with acquired chronic pure red cell aplasia and congenital pure red cell aplasia. However, the treatment of anemia in persons with pure red cell aplasia can contribute to significant morbidity, as follows:

Transfusion therapy can lead to hemosiderosis, and the consequences of iron overload are growth retardation, delay in sexual maturity, cardiac arrhythmias, and cardiac failure. Transfusions can also transmit infections.

Corticosteroid therapy can lead to growth retardation, osteopenia, diabetes, and other complications.

Because of immunotherapy, a small percentage of patients can develop aplastic anemia or acute myelogenous leukemia, and both conditions have high morbidity and mortality rates.

Race

No racial predilection is observed.

Sex

Females are more likely to be affected in immunologically related pure red cell aplasia. However, the male-to-female ratio is 2:1 for pure red cell aplasia associated with thymoma.

Clinical

History

Anemia is the primary problem in pure red cell aplasia. The degree of anemia can range from subclinical to severe. Anemia in acute self-limited pure red cell aplasia is barely noticeable. Profound anemias can also occur in chronic acquired pure red cell aplasia and in congenital pure red cell aplasia. Patients with severe anemias have symptoms and signs of uncompensated anemia and present with weakness, tachycardia, and dyspnea.

Acute self-limited pure red cell aplasia due to viral infections

Often, the patient has a recent history of infectious diseases such as respiratory illnesses or gastroenteritis.

Mumps, infectious mononucleosis, and viral hepatitis often precede the development of acute pure red cell aplasia. Symptoms ascribable to these infectious processes may predominate over those of the transient anemia.

Because the decrease in the hemoglobin (Hgb) level is gradual and self-limited, most cases of acute pure red cell aplasia go unnoticed.

In patients with acute pure red cell aplasia who have hemolytic disorders, anemia can be severe because virtually no production of erythrocytes occurs to compensate for hemolysis. This is known as an aplastic crisis. Under these conditions, patients can develop uncompensated anemia with marked weakness and dyspnea.

Acute self-limited pure red cell aplasia due to drugs

Patients may have a history of taking drugs that can induce pure red cell aplasia.

Having taken a medication for an extended period does not rule out the possibility that the drug is responsible for the episode of acute pure red cell aplasia.

See Causes for a list of medications reported to cause pure red cell aplasia.

Persistent virus- or drug-induced pure red cell aplasia

In some cases of acute pure red cell aplasia due to viral infections or drugs, pure red cell aplasia may persist for a prolonged period.

The following explanations are proposed for this chronicity:

Patients who are immunocompromised cannot mount an adequate defense against viral infections.

Some individuals have an underlying sensitivity to drugs that can induce pure red cell aplasia.

In other patients, an underlying subclinical disorder predisposes patients to prolonged pure red cell aplasia. The acute pure red cell aplasia superimposed on an underlying condition can be severe and prolonged.

A careful history should be taken to elucidate conditions that could lead to this chronicity.

Also, as reported by Musso et al in 2004, it can occur following major ABO-incompatible myeloablative and nonmyeloablative stem cell transplantation.5

Autoimmune disorders may be associated with arthritis.

Thymomas are rarely large enough to be detected during the physical examination.

Lymphadenopathy and splenomegaly may indicate the presence of an underlying lymphoproliferative disorder or systemic lupus erythematosus.

Congenital pure red cell aplasia

Some, but not all, cases of congenital pure red cell aplasia are associated with severe anemias.

In addition to anemia, approximately one third of patients develop physical abnormalities, most often involving the head, upper limbs, thumbs, urogenital system, or cardiovascular system. Growth retardation and unusual thumb formation can occur. However, these physical deformities are less severe than in Fanconi syndrome.

Anemia is not often observed during the early neonatal period, but pallor, weakness, and dyspnea attributable to the anemia develop during the first year of life.

Physical

The signs of anemia and its severity are the major physical findings in persons with pure red cell aplasia. Pallor and weakness are early manifestations. Evidence of a decompensated anemia (eg, dyspnea, tachycardia, incipient heart failure) occurs in those with more severe anemias. Severe anemias can be observed in patients with acute pure red cell aplasia and hemolytic disorders who develop an aplastic crisis. Specific physical findings associated with acute, acquired chronic, and congenital pure red cell aplasia are described below. Also discussed are findings related to possible complications from therapy.

Acute self-limited pure red cell aplasia

Often, physical evidence of anemia is scant or borderline.

Evidence of a recent viral infection (eg, a rash, jaundice in viral hepatitis, splenomegaly in infectious mononucleosis, enlarged parotid glands in mumps) may be present.

In addition to evidence of anemia, patients may have physical findings of underlying thymomas, lymphoproliferative disorders, autoimmune disorders, or immunocompromised states. However, thymomas are rarely large enough to be detected during the physical examination.

Lymphadenopathy and splenomegaly may indicate the presence of an underlying lymphoproliferative disorder.

Anemia is not often recognized during the early neonatal period but is usually apparent during the first 2 years of life.

More than one third of patients have malformations or mental retardation.

Osteogenic carcinoma of the mandible, and abnormalities of the thumbs have been observed.

In general, these physical abnormalities are not as severe as those observed in Fanconi syndrome. Thymomas have not been found in these patients.

Complications of therapy

Iron overload secondary to transfusion therapy can manifest as hyperpigmentation of the skin, arthralgias, cardiac arrhythmia, evidence of endocrinopathies, jaundice due to hepatic dysfunction, and hepatosplenomegaly.

Complications of corticosteroid therapy include retarded growth, diabetes, and osteopenia.

Complications of immunotherapy can include aplastic anemia and acute myelogenous leukemia.

Causes

The etiology of pure red cell aplasia is diverse and is different for the acute self-limited, the acquired chronic (sustained), and the congenital chronic forms of pure red cell aplasia.

Most cases of acute transient pure red cell aplasia are caused by parvovirus B19 infection. Parvovirus B19 can cross the placenta in infected women and can destroy erythroid cells in the fetus; in some cases, the virus can induce spontaneous abortion.

Most drugs believed to cause pure red cell aplasia are thought to do so by exerting a direct toxic effect on RBC precursors. The evidence for drug-induced immunological selective impairment of RBC production is controversial.

Originally, thymoma was cited as the primary cause of acquired pure red cell aplasia. However, subsequent studies revealed that thymomas caused only 2 of 37 cases of pure red cell aplasia. Conversely, only 7% of patients with thymomas had pure red cell aplasia. T-cell–mediated erythroid rejection is considered the mechanism for the production of pure red cell aplasia in patients with thymomas. This is supported by evidence that a subgroup of T cells in B-cell chronic lymphocytic leukemia is responsible for pure red cell aplasia.

Pure red cell aplasia has been associated with autoimmune disorders such as rheumatoid arthritis, systemic lupus erythematosus, autoimmune hemolytic anemia, chronic active hepatitis, collagen-vascular diseases, and chronic lymphocytic leukemia. Immunoglobulin G (IgG) antibodies in sera from many of these patients suppressed the growth of RBC precursors. Evidence indicates that in some cases, acquired chronic pure red cell aplasia can be T-cell mediated. The occurrence and role of autoimmune antibodies against EPO in persons with pure red cell aplasia have not been substantiated.

In patients who are immunocompromised, pure red cell aplasia may be due to persistent parvovirus B19 infections. In healthy persons, an IgG and immunoglobulin M response limits the parvovirus infection, but this response is attenuated in individuals who are immunocompromised.

Approximately 90% of cases are sporadic, and one suggestion is that the sporadic cases are caused by in utero damage to erythroid stem cells. This theory is based on evidence indicating that while Diamond-Blackfan syndrome frequently manifests with random physical abnormalities, it is rarely familial or associated with significant chromosomal abnormalities.

In 10% of patients, a dominant, or more rarely recessive, familial pattern has been observed. One locus on arm 19q13.2 encoding ribosomal protein S19 accounts for a quarter of patients with either the dominant or the sporadic form. Families not linked with this locus have also been described.

Evidence indicates that recombinant EPO can induce pure red cell aplasia in patients with chronic renal failure who had been on dialysis. Thirteen such cases were described by Casadevall et al in 2002 in the New England Journal of Medicine.6 Apparently, additional cases of EPO-related pure red cell aplasia have been noted, bringing the total to approximately 38. Neutralizing anti-EPO antibodies were detected in these patients and considered to be involved in the development of pure red cell aplasia.

The basis for pure red cell aplasia being due to EPO therapy is an enigma. Most of the cases have been reported in France and in patients undergoing renal dialysis. Pure red cell aplasia in these patients is usually severe, and it is unlikely that this would have been overlooked in the United States. Also, EPO-related pure red cell aplasia has only been observed since 1998.

Several possibilities should be considered. EPO used in France may have been manufactured by a different procedure than that used in the United States, and the manner of administration may be different. All patients who developed pure red cell aplasia had been treated with subcutaneous EPO. Although EPO is administered subcutaneously to cancer patients in the United States, EPO is not administered by this route to patients with chronic renal failure in the United States. Home administration of EPO is practiced in Europe but not in the United States. Patients are provided syringes with the appropriate single EPO dose that they keep refrigerated until use, and improper storage may have caused EPO degeneration.

Importantly, note that EPO-related appears to be a rare complication when one considers that approximately 3 million patients are treated with EPO worldwide. Nevertheless, maintain awareness of the possibility of this complication. In 2002, Casadevall et al recommended that patients receiving EPO should be tested for neutralizing anti-EPO antibodies as soon as possible after the onset of an unexplained anemia.6

Patients receiving darbepoetin alfa (Aranesp), which has a different carbohydrate structure than endogenous EPO, should be monitored closely.

Obviously, the administration of EPO for athletic performance should be avoided.

Neutralizing anti-EPO antibodies should be obtained in patients who are not responding to EPO. Following an initial rise in Hgb levels, approximately 20% of patients do not have a sustained response to EPO. Possibly, the generation of anti-EPO antibodies occurs more commonly than suspected. The development of pure red cell aplasia may represent the extreme end of the spectrum of EPO-induced immunological suppression of RBC production.

In 2004, Bennet et al reported that between January 1998 and April 2004, 191 cases of epoetin-associated pure red cell aplasia were reported.7 This occurred primarily with the Eprex brand name of epoetin alfa, and more than half of these cases were reported in France, Canada, the United Kingdom, and Spain. With appropriate procedures for storage, handling, and administration of Eprex to patients with chronic kidney disease, the exposure-adjusted prevalence rate decreased by 83%

anonymous

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May 14, 2010

Pure red cell aplasia is regarded as an autoimmune disease. It may also be a manifestation of thymoma[2] or of viral infections such as HIV, herpes, parvovirus B19 (Fifth disease),[3] or hepatitis. Association of pure red cell aplasia with T large granular lymphocyte leukemia is also well recognized, especially in China.[4] Many cases of PRCA are considered idiopathic in that there is no discernible cause detected.[5]

It can be also associated with the administration of drugs, e.g., erythropoietin[6] or mycophenolic acid.[7]